New research shows that exposure to harmful chemicals and drugs
during critical developmental periods early in life may actually “reprogram” the
way certain genes respond to the female hormone estrogen. This
genetic reprogramming may determine whether people with a genetic
predisposition for a disease actually develop the disease.

The new research shows that when rats with a genetic predisposition
to uterine tumors also receive an early-life exposure to diethylstilbestrol
(DES), a synthetic form of estrogen linked to vaginal cancer, the
incidence of uterine tumors rises to almost 100 percent. By comparison,
slightly more than half of the unexposed animals, those having
only the genetic defect, developed the uterine tumors.

DES is a drug that was prescribed for women from 1938 to 1971
to prevent miscarriages and premature deliveries. Daughters of
women who used DES are at increased risk for reproductive tract
abnormalities, pregnancy complications such as ectopic pregnancies
and preterm deliveries, infertility, and a rare vaginal and cervical
cancer called clear-cell adenocarcinoma. Other research conducted
by NIEHS scientists indicates that women exposed to DES in utero
have a higher risk of uterine fibroids.

The National Institute of Environmental Health Sciences, a component
of the National Institutes of Health, provided funding to researchers
at the University of Texas M.D. Anderson Cancer Center for the
two-year study. The study results will be published in the May
2005 issue of the Proceedings of the National Academy of Sciences.

The discovery is important because it changes conventional thinking
about the way in which genetic predisposition and things in the
environment interact to increase disease risk. Until now, scientists
thought that exposure to harmful agents in the environment caused
damage to the gene. This study, however, indicates that an environmental
agent can actually change or reprogram the gene so that it functions
differently.

“This study is telling us that an environmental reprogramming
of a normal response, combined with an inherited gene defect, work
together to promote cancer,” said NIEHS Director David Schwartz,
M.D. “If this model is correct, it will help doctors to determine
which individuals are more likely to develop cancers of the uterus,
breast and prostate.”

The finding should alert doctors to ask more questions about a
patient’s early-life exposures to chemicals and other harmful
agents in order to better predict that person’s cancer risk.

“Most people with a family history for a particular disease
are concerned about their recent exposures to harmful agents in
the environment,” said Cheryl Walker, Ph.D., professor of
molecular carcinogenesis at the M.D. Anderson Cancer Center and
lead author on the study. “We are just beginning to realize
that exposures received decades earlier, during critical developmental
stages, may be much more important in determining who develops
cancer as an adult.”

The researchers used a special strain of rats with a defect in
a gene called Tsc-2 (tuberous sclerosis complex 2) that made them
more susceptible to uterine leiomyomas, benign tumors that are
common in women over 30 years of age. These rats were then treated
with DES during days 3, 4 and 5 of life, during a critical period
of uterine development.

Once the rats reached adulthood, almost 95 percent had developed
the uterine tumors. Furthermore, the tumors were much larger and
more numerous than those in genetically defective rats not receiving
the DES treatment. “These data suggest that environmental
exposures during development of the uterus can interact with a
preexisting genetic susceptibility to increase the risk of disease,” said
Walker. “We are looking at a new kind of gene-environment
interaction that determines who gets cancer and who doesn’t.”

According to Walker, the increase in frequency and size of the
uterine tumors is due to DES’ ability to influence estrogen,
a female hormone that is involved in promoting the growth of tumors
by regulating the activity of key genes involved in cell growth. “We
found that the DES treatment somehow ‘reprogrammed’ how
these genes respond to estrogen, making them much more responsive
to estrogen than normal,” said Walker. “We realized
that the DES exposure enabled estrogen to drive the tumor development
when combined with a genetic predisposition.”

While DES exposure can lead to the development of vaginal and
cervical cancers, the fact that most DES-exposed women did not
develop the cancers suggests that genetic predisposition is an
important part of the equation. “In most cases, we already
have tests that can determine if a woman has a genetic predisposition
for cancer,” said Walker.

This is not the first study to suggest that cancer risk is influenced
by both genetic and environmental factors. A 2003 study of Jewish
women born with a defect in BRCA1, the gene that is linked to inherited
forms of breast and ovarian cancer, showed that those women born
before 1940 had a much lower risk of developing breast cancer than
women born after 1940. The researchers believe this discrepancy
is due to differences in diet, exercise, hormonal factors and chemical
exposures.

Walker believes more research needs to be done to test this concept
in people. “NIEHS is partnering with the National Academy
of Sciences to fund additional research on early-life exposures
and cancer risk in human populations,” she said.